Branhamella catarrhalis (also known as Moraxella catarrhalis) is an important human respiratory tract pathogen. B. catarrhalis is the third most common cause of otitis media in infants and children, after Streptococcus pneumoniae and nontypeable Haemophilus influenzae, as documented in studies in which tympanocentesis has been used to establish the etiologic agent Murphy, 1989, Pediatr. Infect. Dis. J. 8:S75-S77). B. catarrhalis is a common cause of sinusitis and conjunctivitis in both children and adults (See for example, Bluestone, 1986, Drugs 31:S132-S141; Brorson et al., 1976, Scand. J. Infect. Dis. 8:151-155; and Romberger et al., 1987, South. Med. J. 80:926-928); and is an important cause of lower respiratory tract infections in adults with chronic bronchitis and chronic obstructive pulmonary disease (Murphy et al., 1992, Am. Rev. Respit. Dis. 146:1067-1083; Catlin, 1990, Clin. Microbiol. Rev. 3:293-320). Additionally, B. catarrhalis can cause pneumonia, endocarditis, septicemia, and meningitis in immunocomprised hosts (Cocchi et al., 1968, Acta Paediatr. Scand. 57:451-3; Douer et al., 1977, Ann. Intern. Med. 86:116-119; McNeely et al., 1976, Am. Rev. Respit. Dis. 114:399-402).
Since recurrent otitis media is associated with substantial morbidity, there is interest in identifying strategies for preventing these infections. One such approach is the development of vaccines. An effective vaccine for preventing bacterial otitis media would need to include antigens which would generate protection against infection by S. pneumoniae, nontypeable H. influenzae and B. catarrhalis. Indeed, vaccine development for the pneumococcus and nontypeable H. influenzae are progressing such that potentially protective antigens have been identified and are currently undergoing testing (See for example, Murphy et al., U.S. Pat. No. 5,173,294; and Vella et al., 1992, Infect. Immun. 60:4977-4983). As these vaccines are developed and used more widely, the relative importance of B. catarrhalis as a cause of otitis media will increase in the next decade. Besides infants and children benefitting from a vaccine to prevent otitis media caused by B. catarrhalis, adults with chronic obstructive pulmonary disease, and immunocompromised children and adults would benefit from a vaccine to prevent infections caused by B. catarrhalis.
Bacterial components which have been investigated as potential vaccine antigens include polysaccharides, lipopolysaccharides or modifications thereof, and outer membrane proteins. In general, as exemplified by the type b capsular polysaccharide of H. influenzae, polysaccharide antigens have been shown to be a poor immunogen in children under the age of 18 months. Active immunization with lipopolysaccharide (LPS) is unacceptable due to its inherent toxicity. The pathophysiologic effects of LPS may include fever, leucopenia, leucocytosis, the Shwartzman reaction, disseminated intravascular coagulation, and in large doses, shock and death. In general, proteins are immunogenic in infants around three months of age. Thus, outer membrane proteins are being investigated as possible vaccine antigens.
while recent studies have begun to focus on outer membrane proteins of B. catarrhalis, little is known about the antigenic and molecular structure of these proteins. Studies of purified outer membranes by SDS-PAGE have revealed a rather homogeneous pattern among strains of the bacterium (Bartos and Murphy, 1988, J. Infect. Dis. 158:761-765). Eight major outer membrane proteins, designated by the letters A-H, have been identified (Murphy et al., 1989, Microbial Pathogen. 6:159-174; Bartos et al., 1988, J. Infect. Dis. 158: 761-765). Outer membrane proteins C and D differ slightly in apparent molecular mass, and thus appear as a doublet on SDS-PAGE electrophoresis. Monoclonal antibodies have been developed to B. catarrhalis resulting in two monoclonal antibodies, 7D6 and 5E8, which recognized both proteins C and D (Sarwar et al., 1992, Infect. Immun. 60:804-809). Prior to the development of the present invention, it was unknown whether this doublet represented a single protein (CD) with two stable conformations, or whether C and D are two closely related proteins encoded by different genes (Sarwar et al., supra). Proteins C and D are of interest, particularly for vaccine development, because these proteins express at least one conserved epitope on the surface of intact B. catarrhalis (Satwar et al., 1992, supra).
Hence, with the increasing recognition of B. catarrhalis as an important bacterial pathogen, there is a need for a vaccine that is immunogenic in children and adults. Such a vaccine would have to be directed to a bacterial component which has a surface-exposed epitope on intact bacteria, wherein the epitope is conserved amongst strains of B. catarrhalis.